Sustained or prolonged-release dosage forms provide a controlled and constant supply of drug to an organism. The control of cough, sleep, enuresis, and migraine headaches are all benefits obtained from such a controlled release of a specific drug. Additionally, controlled release of antimicrobials can be obtained through such a dosage form. Such controlled release drugs eliminate the need to interrupt sleep to take medication, and can also prevent missed doses. They also provide the convenience of daytime dosing where the dosage form can be taken first thing in the morning and provide therapeutic levels of the drug throughout the day.
A controlled drug-release system delivers drugs in a manner that will maintain therapeutically effective plasma levels over a period of time that is significantly longer than that which is given by a typical drug dosage form.
Uncoated ion-exchange resin-drug complexes which delay release of a drug in the gastrointestinal tract are described in U.S. Pat. No. 2,990,332. However, such uncoated complexes provide only a relatively short delay of drug release in comparison with the preparations of this invention and provide poor control of drug release because the control is limited to variation in particle size and cross-linkage of the sulfonic acid-type resin used to prepare the adsorption compounds.
Various coated resin-drug complexes have been reported (e.g., in U.S. Pat. Nos. 3,138,525; 3,499,960 and 3,594,470; Belgian Pat. No. 729,827; German Pat. No. 2,246,037; and Borodkins et al, Journal of Pharmaceutical Science. Vol. 60, pages 1523-1527, 1971), but none are believed to employ the preparations of the subject invention or to provide the prolonged continuous release obtainable with the present preparations.
The present invention provides controlled-release pharmaceutical compositions obtained by complexing the drug with a pharmaceutically acceptable ion-exchange resin and coating such complexes with a substance that will act as a barrier to control the diffusion of the drug from its core complex into the gastrointestinal fluids.
It is known that the pharmaceutically acceptable resins and their drug complexes can undergo significant swelling (up to about a 60% increase in volume) when the dry, non-hydrated form is placed in contact with gastrointestinal fluids.
When the coated drug-resin complex is suspended in an aqueous dosage form or when it contacts gastrointestinal fluids, it expands to its swollen state, and in doing so, ruptures the diffusion barrier coating. The result is loss of control of the diffusion of released drug.
Controlled-release drugs for use in the gastrointestinal tract are described in U.S. Pat. No. 4,221,778 to Raghunathan, issued Sept. 9, 1980. The method described therein for preparing products having controlled release properties involved a three-step process: (i) preparation of a drug-resin complex; (ii) treating this complex with a suitable impregnating agent; and (iii) coating the particles of treated complex with a water-permeable diffusion barrier. The impregnation is necessary to provide the desired controlled-release of drug.
The present invention does not require any such impregnation and provides a coated drug-resin complex which, when placed in contact with an aqueous vehicle or with gastrointestinal fluids, does not undergo swelling sufficient to rupture the diffusion barrier coating. Without being limited by theory, Applicants have demonstrated that there is a critical drug load that must be achieved in order to assure maintenance of the integrity of the coating and therefore controlled release of the drug active.
It is therefore an object of the present invention to provide a drug-resin complex coated with a water-permeable diffusion barrier coating that is insoluble in gastrointestinal fluids thereby providing a controllable sustained release of drug under conditions encountered in the gastrointestinal tract.
It is a further object of the present invention to provide such a coated drug-resin complex which does not undergo swelling sufficient to rupture its diffusion barrier coating.